Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population

Abstract

BackgroundMethotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA.MethodsTen polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and−43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and−401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR).ResultsComparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH−401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1−43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients.ConclusionThe variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis

“…However, few studies have examined the relationship between RFC-1 SNP and RA. In the present study, we detected no difference in genotypes and allele frequencies of MTHFR C677T and A1298C and RFC-1 A80G between patients with RA (cases) and controls, indicating that these polymorphisms were not associated with RA susceptibility in the Henan Han population, consistent with the results of Gonzalez-Mercado et al 15 and Hashiguchi et al 16 MTX, as a DMARD, is the first-line anchor drug for treating RA. It plays a role in the folate transport pathway by inhibiting the key enzymes.…”

The impacts of gene polymorphisms on methotrexate in Chinese psoriatic patients

“…However, few reports have been focused on the association between gene polymorphisms and MTX efficacy. Previous studies have shown that ABC transporter family members are associated with MTX efficacy, including polymorphisms in the ABCC1 , and ABCG2 genes, and other genetic polymorphisms of RFC‐1 , 49,50 MTHFR , 51,52 ATIC, 53 FPGS 54 and FOXP3 55 . Except for ABCB1 (rs1045642), no other gene polymorphisms were found to be associated with the effectiveness of MTX in this study.…”

Enzymes involved in folate metabolism and its implication for cancer treatment

“…However, in Korean patients with cervical cancer who underwent radical hysterectomy, a poor response to platinum-based neoadjuvant chemotherapy was associated with the CC genotype of -401C>T, which might be attributed to the counteractive effects of CC genotypes of XRCC1 A194T and GGH -401C>T in cervical cancer [77]. Furthermore, there was an interethnic difference in the GGH 452 T allelic frequency-14% in Caucasian, 9-10% in Asian, and 8% in African population groups [75]. GGH +452C>T was associated with low GGH activity and high MTX polyglutamate accumulation in ALL patients [78].…”

“…-401C>T and -124T>G showed enhanced GGH expression in MCF7 human breast cancer cells, suggesting that polymorphisms in the GGH gene promoter may increase GGH expression [74]. Moreover, the GGH-401 T allele frequency varied among ethnic or populations groups in healthy adults-22-36% in Asian, 31% in Caucasian, and 14% in African population groups [75]. In RA patients, patients with the TT genotype of -401C>T were associated with higher GGH activity compared to patients with CC or CT genotypes, indicating that the TT genotype might be related to poor response to antifolates [76].…”